Segment polarity genes were originally discovered as mutations in flies that change the pattem of body segment structures. Among the genes in this class are hedgehog, patched, and costal2. The proteins encoded by these genes form a signaling pathway that regulates key events in early development, and in adult life has been implicated in carcinogenesis. The pathway has been best studied in model organisms such as flies, but it is conserved among all animals. In this pathway, the secreted signaling protein hedgehog binds to its receptor, patched, on receiving cells. Costal2 is part of the machinerythat then transduces this signal to the nucleus, resulting in changes in gene activation.
Hedgehog induces transcription of certain powerful regulatory target genes, while both patched and costal2 act in opposition to keep the target genes turned off. Other components of the pathway required for activation include the seven transmembrane protein, smoothened, the kinase fused, and cubitus inteffuptus. Experimental data suggests that hedgehog binds to patched at the cell surface, preventing patched from inactivating smoothened function. In the presence of hedgehog signal, smoothened is active, allowing it to send an activating signal to the nucleus. How hedgehog and smoothened send the activating signal to the nucleus is unknown, but genetic evidence suggests that fused and costal2 are involved. Changes in their activities are thought to allow cubitus interruptus to directly activate the transcription of hedgehog target genes.
The hedgehog signaling pathway has been implicated in several important human disease processes. For example, mutations in patched are associated with basal cell carcinomas, developmental abnormalities and brain tumors. The human homolog of cubitus interruptus, GLI, is an oncogene found in gliomas. One of the human hedgehog homologs, SHH, has also been implicated in tumorigenesis.
The characterization and identification of hedgehog signaling pathway component genes is of great interest, because of their involvement in the control of cellular differentiation and growth regulation.